INCREASED HEPATIC LYSOSOMAL ACTIVITY IN BILIARY-CIRRHOSIS ORIGINATES FROM HEPATOCYTES RATHER THAN FROM MACROPHAGES

To investigate the potential role of lysosomes in cirrhosis, the activ ity of lysosomal enzymes was analyzed in rats with cirrhosis induced b y bile-duct ligation. Twenty-eight days after surgery, the activity of lysosomal enzymes was markedly increased in the homogenate of cirrhot ic livers (e.g. arylsulfatase 7+/-SD 1 vs 17+/-3 nmol.min(-1).mg(-1) i n controls and cirrhotics, respectively; p<0.001). The corresponding p lasma levels were also increased (arylsulfatase: 10+/-1 vs 25+/-9 pmol .min(-1).mg(-1); p<0.01). In contrast, the activities of these enzymes in lysosomal fractions did not differ, suggesting an increase in numb er of lysosomes. The increased lysosomal activity correlated with seve rity of cirrhosis as assessed by the aminopyrine breath test and with cholestatic parameters but less with transaminases. Since macrophages, cells which are rich in lysosomes, could contribute to the increase i n lysosomal enzyme content, these cells were estimated stereologically after being marked immunohistochemically with a monoclonal antibody a gainst the rat macrophage membrane antigen ED2. ED2 positive cells wer e increased 2.7-fold in cirrhotic livers. This increase cannot account for the observed increase in hepatic lysosomal enzyme content. Furthe rmore, 1 week after bile-duct ligation, when there was cholestasis but not yet cirrhosis, lysosomal enzyme activities were already increased . These data support the idea that the increased hepatic lysosomal act ivity in biliary cirrhosis is of hepatocyte rather than of macrophage origin, and is presumably related to cholestasis. (C) Journal of Hepat ology.